1. Field of the Invention
This invention relates to the stabilization of radiolabeled compounds, such as amino acids and nucleosides and particularly to certain thiocarbonylated amines useful for stabilizing such radiolabelled compounds.
2. Description of the Prior Art
An increasing number of radiolabeled compounds are being used in research for medical diagnosis and various other areas. However, the radiolytic decomposition of such compounds has been a constant problem. Without the addition of some type of stabilizer, a solution of such a compound may become unusable due to decomposition within a matter of weeks or less. This radiolytic decomposition of such compounds has been studied extensively. For example, the radiation chemistry of amino acids is reviewed in an article by J. Liebster and J. Kopeldova, Radiation Biol., 1, 157 (1964) and the self-decomposition of radioactively labeled compounds is discussed in Atomic Energy Review, 10, 3-66 (1972), both of which are hereby incorporated herein by reference.
Although certain specific compounds have been suggested for stabilization, problems still exist. The latter article reviews the underlying causes and mechanisms of self-decomposition, "which are very complex and in some cases not well understood." (At pg. 3). After discussing the principal mechanisms by which decomposition occurs, the article notes generally at page 36 that buffers such as ammonium bicarbonate help to stabilize radiolabeled compounds, but care must be taken to insure that the buffer chosen does not interfere with the later use of the labeled compound. For example, phosphate buffers would interfere with phosphorylation reactions. Other compounds which have been suggested at various times are listed at page 35 and include benzyl alcohol, glycerol, cysteamine, and sodium formate. However, each of these are said to suffer due to their difficulty of removal. Another compound mentioned is ethanol which is said to work with many compounds. However, ethanol sometimes actually sensitizes certain nucleosides to radiation decomposition and thus it has been found not to be a universal panacea. Furthermore, if it will interfere with the reaction in which the radiolabeled compound is to be used, the ethanol must be removed by evaporation which may also contribute to decomposition.
Various compounds are suggested in Atomic Energy Review, above, for stabilization of radiolabeled compounds prone to oxidation including antioxidants such as butylated-hydroxytoluene, butylated-hydroxyanisole and mercaptoethanol. While not mentioned for use with radiolabeled compounds, the inhibition of autoxidation generally by certain amines has also been described in the prior art. Recent reviews on the inhibition of autoxidation are "Autoxidation" by R. Stroh, pg, 1049 in, Methoden der Organischen Chemie (Houben-Weyl), ed. E. Muller and O. Bayer, Vol. IV/Ib Oxidation II., Georgthieme Verlag, 1975, and Encyclopedia of Chemical Technology, Kirk Othmer, Interscience Publishers, New York. The utility of secondary dialkyl amines bearing full alpha-substitution (i.e., containing no hydrogens on the carbon atoms adjacent to the nitrogen) and secondary diarylamines (also without alpha-hydrogens) as antioxidants is known. However, the use of primary, secondary and tertiary amines, those containing alpha-hydrogens, in this regard is not known and, in fact, it has been suggested that such amines are not effective for this purpose. Such antioxidants have many of the same problems as other of the compounds discussed above, including, in addition, generally being insoluble in the solvents used to dissolve and store radiolabeled compounds for use in biological studies.
U.S. Pat. No. 3,876,550 describes lubricant compositions to improve the anti-oxidant and rust inhibiting properties of such lubricant compositions. The additive combination includes alkylene dithiocarbamate, but does not contain any suggestion for the use of such compounds as stabilizers for radiolabeled compounds.
V. S. Etlis et al., "Synthesis and Anti-Radiation Properties of Polymeric Dithiocarbamates", Khimiko-Farmatsevticheskii Zhurnal, Vol. 10, no. 4 pp. 33-35, April (1976) describes the synthesis and preparation of water soluble polymeric sodium and ammonium dithiocarbamates, indicates that they are useful as radiation protectors, and reports testing of such compounds in mice for protection against irradiation with Co.sup.60 (1000 R, intensity 26-30 R/sec.) However, these compounds are not indicated as having any activity as stabilizers of radiolabeled compounds.
J. Barnes et al., Eur. J. Med. Chem.--Chimica Therapeutica, Nov. Dec. (1975) -10, No. 6, pgs. 619-622, describes sodium salts of alkenebisdithiocarbamates and aminoalkyldithiocarbamic acids for use as radiation protection agents. The compounds were tested in mice for use as radio-protectors. Particular attention is called to compound No. 11 in Table 1 on page 620, the preparation of which is described on page 621 in the paragraphs immediately below Table 2. It is believed that the structure of compound 11 is incorrectly identified. There is no disclosure or suggestion in Barnes et al., for employing any of the compounds therein for the stabilization of radiolabeled compounds and solutions.
U.S. application Ser. No. 105,272, filed Dec. 19, 1979 now U.S. Pat. No. 4,358,434 and U.S. Ser. No. 178,609, filed Aug. 15, 1980, both of which are incorporated herein by reference, disclose the stabilization of radiolabeled compounds by adding to solutions of such compounds a compound having a substantially insoluble backbone, preferably a resin, such as an ion exchange resin, to which has been bound a quaternary ammonium group; or a water soluble primary, secondary or tertiary aliphatic amine which does not interfere with the use contemplated for the particular radiolabeled compound being stabilized.